Formation of N-protected bis-3,6-(4-aminobutyl)-2, 5-diketopiperazine through a cyclic alpha-N-protected amino ester

ABSTRACT

A method for the synthesis of N-protected 3,6-aminoalkyl-2,5-diketopiperazines is provided. The method includes obtaining a cyclic α-N protected active amino ester and adding it to a mixture of an amine catalyst in an organic solvent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This non-provisional patent application claims the benefit of U.S.non-provisional application Ser. No. 14/629,046, filed Feb. 23, 2015,which in-turn claims the benefit of U.S. non-provisional applicationSer. No. 14/212,957, filed Mar. 14, 2014, now U.S. Pat. No. 8,962,836issued on Feb. 24, 2015, which in-turn claims the benefit of U.S.provisional application No. 61/798,016, filed Mar. 15, 2013, the contentof which are hereby incorporated by reference as if recited herein intheir entirety.

TECHNICAL FIELD

The present invention relates to compositions for delivering activeagents, and particularly biologically active agents. Disclosedembodiments are in the field of chemical synthesis and more particularlyare related to improved synthetic methods for the preparation ofsubstituted diketopiperazines.

BACKGROUND

Drug delivery is a persistent problem in the administration of activeagents to patients. Conventional means for delivering active agents areoften severely limited by biological, chemical, and physical barriers.Typically, these barriers are imposed by the environment through whichdelivery occurs, the environment of the target for delivery, or thetarget itself.

Biologically active agents are particularly vulnerable to such barriers.For example in the delivery to humans of pharmacological and therapeuticagents, barriers are imposed by the body. Examples of physical barriersare the skin and various organ membranes that must be traversed beforereaching a target. Chemical barriers include, but are not limited to, pHvariations, lipid bi-layers, and degrading enzymes.

These barriers are of particular significance in the design of oraldelivery systems. Oral delivery of many biologically active agents wouldbe the route of choice for administration to animals if not forbiological, chemical, and physical barriers such as varying pH in thegastrointestinal (GI) tract, powerful digestive enzymes, and activeagent impermeable gastrointestinal membranes. Among the numerous agentswhich are not typically amenable to oral administration are biologicallyactive peptides, such as calcitonin and insulin; polysaccharides, and inparticular mucopolysaccharides including, but not limited to, heparin;heparinoids; antibiotics; and other organic substances. These agents arerapidly rendered ineffective or are destroyed in the gastrointestinaltract by acid hydrolysis, enzymes, or the like.

Earlier methods for orally administering vulnerable pharmacologicalagents have relied on the co-administration of adjuvants (e.g.,resorcinols and non-ionic surfactants such as polyoxyethylene oleylether and n-hexadecylpolyethylene ether) to increase artificially thepermeability of the intestinal walls, as well as the co-administrationof enzymatic inhibitors (e.g., pancreatic trypsin inhibitors,diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymaticdegradation.

Liposomes have also been described as drug delivery systems for insulinand heparin. See, for example, U.S. Pat. No. 4,239,754; Patel et al.(1976), FEBS Letters, Vol. 62, pg. 60; and Hashimoto et al. (1979),Endocrinology Japan, Vol. 26, pg. 337.

However, broad spectrum use of drug delivery systems is precluded due toa variety of reasons including: (1) the systems require toxic amounts ofadjuvants or inhibitors; (2) suitable low molecular weight cargos, i.e.active agents, are not available; (3) the systems exhibit poor stabilityand inadequate shelf life; (4) the systems are difficult to manufacture;(5) the systems fail to protect the active agent (cargo); (6) thesystems adversely alter the active agent; or (7) the systems fail toallow or promote absorption of the active agent.

More recently, microspheres of artificial polymers of mixed amino acids(proteinoids) have been used to deliver pharmaceuticals. For example,U.S. Pat. No. 4,925,673 describes drug-containing proteinoid microspherecarriers as well as methods for their preparation and use. Theseproteinoid microspheres are useful for the delivery of a number ofactive agents.

There is still a need in the art for simple, inexpensive deliverysystems which are easily prepared and which can deliver a broad range ofactive agents. One class of delivery system that has shown promise isdiketopiperazines. In particular, 3,6-bis-substituted diketopiperazineshave been shown to effectively deliver biologically active agents acrossthe lining of the lung.

SUMMARY

This and other unmet needs of the prior art are met by compounds andmethods as described in more detail below. The use of3,6-aminoalkyl-2,5-diketopiperazines as pharmaceutical excipients hasshown considerable promise. As mentioned above, diketopiperazines areoften synthesized via cyclocondensation of amino acids. If the aminoacid has a free nitrogen on its side-chain (as in, for example, lysineor ornithine) it is often necessary to have this nitrogen blocked priorto the cyclization reaction. Compound 1 below shows an example of aN-protected amino acid. Cyclocondensation of 1, under appropriateconditions, then gives compound 2.

Because of the potential for disparate synthetic processes afterdiketopiperazine formation, compatibility with a variety of protectinggroups is desired. Thus a synthetic method that can accommodate a numberof diverse N-protecting groups and produce good yield of N-protecteddiketopiperazine is desired. However, the cyclocondensation shown oftenrequires high temperatures or harsh conditions to achieve fullcyclization. Further, it is not compatible with each N-protecting groupthat might be necessary for further derivatization of the exo-cyclicnitrogens.

Some useful N-protecting groups include acetyl, trichloroacetyl,trifluoroacteyl and other amide forming protecting groups; carbamateprotecting groups including benzyloxycarbonyl (Cbz) and t-butoxycarbonyl(BOC) among others.

In an embodiment, a method for the synthesis of a3,6-aminoalkyl-2,5-diketopiperazine is provided. The method comprises,adding a cyclic α-N protected active amino ester according to theformula below:

wherein R₁ is a N-protected amino C₁ to C₈ alkyl, and X is C, S or P, toa mixture of an amine catalyst in an organic solvent.

In an embodiment, a method for the synthesis of a3,6-aminoalkyl-2,5-diketopiperazine is provided. The method comprises,adding a cyclic α-N protected active amino ester to a mixture of anamine catalyst in an organic solvent. In certain embodiments, the methodprovides 3,6-aminoalkyl-2,5-diketopiperazine in a yield of greater than40% (i.e., 40 to 100%).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a reaction scheme showing an exemplary embodiment of a routefor the formation of 3,6-aminoalkyl-2,5-diketopiperazine through acyclic N-carboxy anhydride (NCA) intermediate.

FIG. 2 is a bar graph showing results for a survey of several organicsolvents.

FIG. 3 is a bar graph showing results for several experiments usingtemperature as a variable.

FIG. 4 is a bar graph showing results for several experiments usingaddition time as a variable.

FIG. 5 is a bar graph showing results for several experiments usingcatalyst level as a variable.

FIG. 6 is a bar graph showing results for several experiments using theparticular catalyst as a variable.

FIG. 7 is a bar graph showing results for several experiments usingreaction time as a variable.

DETAILED DESCRIPTION

As used herein, the following terms should be understood as follows:methyl, ethyl, n-Propyl, isopropyl, n-Butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, heptyl or octyl and all bond isomers are tobe considered as (C₁-C₈)-alkyl. These can be mono- or poly-substitutedwith (C₁-C₈)-alkoxy, (C₁-C₈)-haloalkyl, OH, halogen, NH₂, N0₂, SH,S—(C₁-C₈)-alkyl.

(C₂-C₈)-alkenyl, with the exception of methyl, is understood to mean a(C₁-C₈)-alkyl group as illustrated above having at least one doublebond.

(C₂-C₈)-alkynyl, with the exception of methyl, is understood to mean a(C₁-C₈)-alkyl group as illustrated above, having at least one triplebond.

(C₃-C₈)-Cycloalkyl is understood to mean cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl groups etc. These may besubstituted with one or more halogens and/or groups containing N—, 0-,P-, S-atoms and/or may have groups containing N-, 0-, P-, S-atoms in thering, such as e.g., 1-, 2-, 3-, 4-piperidyl, 1-, 2-, 3-pyrrolidinyl, 2-,3-tetrahydrofuryl, 2-, 3-, 4-morpholinyl. These can also be mono- orpoly-substituted with (C₁-C₈)-alkoxy, (C₁-C₈)-haloalkyl, OH, C₁, NH₂,N0₂.

A (C₆-C₁₈)-aryl group is understood to be an aromatic group with 6 to 18C-atoms. These include in particular compounds such as phenyl-,naphthyl-, anthryl-, phenanthryl-, biphenyl groups. It can be mono- orpolysubstituted with (C₁-C₈)-alkoxy, (C₁-C₈)-haloalkyl, OH, halogen,NH₂, N0₂, SH, S—(C₁-C₈)-alkyl.

A (C₇-C₁₉)-aralkyl group is a (C₆-C₁₈)-aryl group bound to the moleculeby a (C₁-C₈)-alkyl group.

(C₁-C₈)-alkoxy is a (C₁-C₈)-alkyl group bound to the molecule underconsideration by an oxygen atom.

(C₁-C₈)-haloalkyl is a (C₁-C₈)-alkyl group substituted with one or morehalogen atoms.

A (C₃-C₁₈)-heteroaryl group means, in the context of the invention, afive-, six-, or seven-link aromatic ring system of 3 to 18 C atoms,which has heteroatoms such as nitrogen, oxygen or sulfur in the ring.Groups such as 1-, 2-, 3-furyl, such as 1-, 2-, 3-pyrrolyl, 1-, 2-,3-thienyl, 2-, 3-, 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7-indolyl, 3-, 4-,5-pyrazolyl, 2-, 4-, 5-imidazolyl, acridinyl, chinolinyl,phenanthridinyl, 2-, 4-, 5-, 6-pyrimidinyl are considered in particularto be such heteroatoms. It can be mono- or poly-substituted with(C₁-C₈)-alkoxy, (C₁-C₈)-haloalkyl, OH, halogen, NH₂, N0₂, SH,S(C₁-C₈)alkyl.

A (C₄-C₁₉)-heteroaralkyl is understood to be a heteroaromatic systemcorresponding to the (C₇-C₁₉) aralkyl group.

The term (C₁-C₈)-alkylene unit is understood to mean a (C₁-C₈)-alkylgroup, which is bound to the relevant molecule by two of its C atoms. Itcan be mono- or poly-substituted with (C₁-C₈)-alkoxy, (C₁-C₈)-haloalkyl,OH, halogen, NH₂, N0₂, SH, S—(C₁-C₈)-alkyl.

Fluorine, chlorine, bromine and iodine may be considered as halogens.

A side-chain group of an α-amino acid is understood to mean thechangeable group on the a-C atom of glycine as the basic amino acid.Natural-amino acids are given for example in Bayer-Walter, Lehrbuch derorganischen Chemie, S. Hirzel Verlag, Stuttgart, 22nd edition, page822ff.

Preferred synthetic α-amino acids are those from DE 19903268.8. The sidechain groups can be derived from those referred to there.

The stated chemical structures relate to all possible stereoisomers thatcan be obtained by varying the configuration of the individual chiralcenters, axes or surfaces, in other words all possible diastereomers aswell as all optical isomers (enantiomers) falling within this group.

As mentioned above, diketopiperazines are often synthesized viacyclocondensation of amino acids. If the amino acid has a free nitrogenon its side-chain (as in, for example, lysine or ornithine) it is oftennecessary to have this nitrogen blocked prior to the cyclizationreaction. Compound 1 below shows an example of a N-protected amino acid,wherein PG is a protecting group and n denotes a C₁-C₈ alkyl.Cyclocondensation of Compound 1, under appropriate conditions, thengives Compound 2.

Because of the potential for disparate synthetic processes afterdiketopiperazine formation, compatibility with a variety of protectinggroups is desired. Thus a synthetic method that can accommodate a numberof diverse N-protecting groups and produce good yield of N-protecteddiketopiperazine is desired. However, the cyclocondensation shown aboveoften requires high temperatures or harsh conditions to achieve fullcyclization. Further, this cyclocondensation is not compatible with eachN-protecting group that might be necessary for further derivatization ofthe exo-cyclic nitrogens (the protected nitrogens).

Some useful N-protecting groups include acetyl, trichloroacetyl,trifluoroacetyl and other amide forming protecting groups; carbamateprotecting groups including benzyloxycarbonyl (Cbz) and t-butoxycarbonyl(Boc) among others.

In an embodiment, a method for the synthesis of a3,6-aminoalkyl-2,5-diketopiperazine is provided. The method comprises,adding a cyclic amino ester according to Compound 3.

wherein R₁ is a N-protected amino C1 to C8 alkyl, and X is C, S or P, toa solution of an amine catalyst in an organic solvent.

In an embodiment a method for the synthesis of a N-protected3,6-bis-aminoalkyl-2,5-diketopiperazine of formula I is provided.

The method comprises adding a N-protected cyclic alkyl amino acidaccording Formula II.

to a mixture of an amine catalyst in an organic solvent, the aminecatalyst selected from the group comprising: aziridine andbenzamidoxime.

In certain embodiments, the PG is selected from CBz, Boc,trifluoroacetyl, acetyl and other carbamate and amid forming protectinggroups, X is selected from C, S and P, and n is equal to 1 to 8.

In certain embodiments, the synthesis of the diketopiperazine isperformed in an organic solvent. Suitable organic solvents include polarorganic solvents and non-polar organic solvents. In certain embodiments,the solvent is selected from THF, acetonitrile, dioxane, and ethanol.

In certain embodiments, the synthesis of the diketopiperazine isperformed in an organic solvent. Suitable organic solvents include polarorganic solvents and non-polar organic solvents. In certain embodiments,the solvent is selected from THF and ethanol.

In certain embodiments, the disclosed methods provide a3,6-aminoalkyl-2,5-diketopiperazine in a yield of greater than 40%(i.e., 40 to 100%). In certain embodiments, the disclosed methodsprovide a 3,6-aminoalkyl-2,5-diketopiperazine in a yield of greater than50% (i.e., 50 to 100%). In certain embodiments, the disclosed methodsprovide a 3,6-aminoalkyl-2,5-diketopiperazine in a yield of greater than55% (i.e., 55 to 100%) or more.

In certain embodiments, the disclosed methods provide a3,6-aminoalkyl-2,5-diketopiperazine having a purity of greater than 70%(i.e., 70 to 100%). In certain embodiments, the disclosed methodsprovide a 3,6-aminoalkyl-2,5-diketopiperazine having a purity of greaterthan 80% (i.e., 80 to 100%). In certain embodiments, the disclosedmethods provide a 3,6-aminoalkyl-2,5-diketopiperazine having a purity ofgreater than 90% (i.e., 90 to 100%) or more.

As previously mentioned, in certain embodiments, compounds according toFormula II react to form diketopiperazines of Formula I. In certain suchembodiments, the compounds of Formula II react with an amine catalyst.Non-limiting examples of amine catalysts according to the disclosedembodiments include cyclic alkyl amines such as aziridine, andamidoximes such as benzamidoxime. Other catalysts useful according tothe methods disclosed herein include: 4-nitrobenzamidoxime,hydroxysuccinimide, p-nitrophenol, and hydroxybenzotriazole.

In embodiments wherein the amine catalyst is a cyclic alkyl amine, thediketopiperazine according to Formula II may be obtained by adding thecyclic α-N protected active amino ester intermediate according to themethod discussed by Rosenmund et al., Angew Chem. Internat. Edit. Vol. 9(1970), the content of which is incorporated by reference as if fullyrecited herein. In embodiments wherein the amine catalyst is anamidoxime, the diketopiperazine according to Formula II may be obtainedby adding the cyclic α-N-protected active amino ester intermediateaccording to the method discussed by Buijle et al., U.S. Pat. No.3,407,203, the content of which is hereby incorporate by reference as iffully recited herein.

As mentioned previously, a variety of protecting groups are contemplatedfor use according to the embodiments disclosed herein. When employingthe protecting groups mentioned above, it is advantageous to provide theN-protecting group to the amino acid, prior to cyclization into thecyclic α-N-protected active amino ester intermediates of Compound 3. Incertain embodiments according to compound 3, X is C, R is an N-protectedalkyl amine. Thus giving compounds such as compound 4

Where PG is trifluoroacetyl, CBz, Boc, acetyl, and n is equal to 1-7.Cyclization of compounds according to structure 4 would thus providediketopiperazines according to structure 2 above, where PG istrifluoroacetyl, CBz, Boc, acetyl, and n is equal to 1-7.

The cyclic α-N-protected active amino ester intermediates of Compound 4can be obtained according to a variety of methods. In certainembodiments, the cyclic α-N-protected active amino ester can be obtainedvia reaction of the N-protected amino acid with phosgene underappropriate conditions. For example, Blacklock et al., provide aprocedure for the cyclization N′-(Trifluoroacetyl)-L-lysine (compound 1,PG=TFA, n=3). J. Org. Chem., Vol. 53 (4), 1988, the content of which ishereby incorporated by reference as if fully recited herein. Thus, incertain embodiments, a cyclic α-N-protected active amino ester isobtained by addition of a solution of N-protected amino acid to a cooledsolution of phosgene in an organic solvent. In embodiments where X is S,phosgene is replaced with thionyl chloride to give structure such ascompound 3.

In certain embodiments, the diketopiperazine synthesized is Compound 5:

In certain other embodiments, the diketopiperazine synthesized isCompound 11:

In certain other embodiments, it is contemplated that the PG is removedafter formation of the diketopiperazine ring, and optionally, prior toisolation from the reaction. In such embodiments, the diketopiperazineso obtained would correspond to compound 6, PG is H, and n is 3, or:

EXAMPLES

FIG. 1 shows a reaction scheme for the production of Compound 11, via acyclic α-N-protected active amino ester (CBz-Lys-NCA shown in FIG. 1).CBz-Lys-NCA, was synthesized according to the following procedure:triphosgene (26.49 g), CBz-Lys (50.00 g), and tetrahydrofuran (THF) (500mL) were charged to a 1 L, 4-neck, round bottomed flask fitted with anitrogen purge, a mechanical stirrer, a condenser and a thermocouple.The reaction mixture was heated to 35-38° C. until clear. The reactionmixture was cooled to ambient temperature, and nitrogen was bubbledthrough it to remove any excess phosgene. The solvent was then removedin vacuo. The crude product was crystallized from THF (200 mL) andhexane (125 mL). The resulting white solid was isolated by filtrationand dried overnight in vacuo. Yield of CBz-Lys-NCA was 48.6 g (89.02%).

Once the CBz-Lys-NCA was obtained, it was used to generate Compound 11according to the following: benzamidoxime catalyst (3.33 g) and THF (50mL) were charged to a 250 mL, 3-neck flask fitted with a nitrogen purge,a magnetic stir bar, a thermocouple, and a 60 mL addition funnel.CBz-Lys-NCA (5.00 g) was slurried in THF (50 ml), then added to thecatalyst in THF dropwise over 2 hr. The reaction mixture was stirred atambient temperature overnight, then poured into 100 mL of deionizedwater. The resulting white solid was isolated by filtration, and driedovernight at 50° C. in vacuo. Crude 11 yield was 3.41 g (79.7%). PureCompound 11 yield (from CBz-Lys-NCA) was 75.8% after recrystallization.

A series of solvents (THF, acetonitrile, dioxane and acetone) wereevaluated for the step of converting the CBz-Lys-NCA to Compound 11. Ascan be seen from FIG. 2, acetonitrile, THF, and dioxane gave Compound 11in comparable yield and purity. However, acetone was judged unacceptablebecause the reaction produced a viscous yellow material that could notbe isolated by filtration.

The effects of temperature (1-75° C.) were also evaluated. THF was usedas the reaction solvent, except for the reaction conducted at 75° C.,which used acetonitrile. As can be seen from FIG. 3, the highestCompound 11 yield was obtained at 50° C. Purity was unaffected by thiselevated temperature. At low temperature (1° C.), high mass recovery wasobserved, but the quality of the material was low (55.2 wt % purity).

The rate of CBz-Lys-NCA was varied from 0 to 240 min. As can be seenfrom FIG. 4, longer addition times gave better Compound 11 yield withoutnegatively impacting purity. When the CBz-Lys-NCA was added in oneportion (0 min. addition time), high mass recoveries were observed, butthe material quality was low (71.7 wt %).

FIG. 5 shows the results of experiments testing the amount ofbenzamidoxime in the reaction. The benzamidoxime charge was varied from0.25 to 2.5 eq. (based on the CBz-Lys-NCA charge). FIG. 5 shows that the1.5 equivalents of benzamidoxime provided the best Compound 11 yieldwithout negatively impacting wt % purity.

FIG. 6 shows the results of experiments testing four additionalcompounds for their use as catalysts for the general reaction shown inFIG. 1. In FIG. 6, A=benzamidoxime; B=hydroxysuccinimide (HO-Su);C=4-nitrobenzamidoxime; D=p-nitrophenol; E=hydroxybenzotriazole HOBT,note, the reactions using p-nitrophenol and HOBT produced no product. Ascan be seen from FIG. 6, the use of HO-Su gives Compound 11 in betteryield but lower purity than benzamidoxime. The other catalysts screenedresulted in either low purity (4-nitrobenzamidoxime) or no product(p-nitrophenol and HOBT). Using 0.2 equivalents of either HOBT or HO-Suas a co-catalyst with 1.0 equivalent of benzamidoxime gave an improvedyield of lower-purity Compound 11.

FIG. 7 shows the results of experiments wherein the reaction timefollowing addition of CBz-Lys-NCA was varied from 2 to 22.5 hr. As canbe seen from FIG. 7, 2 hours was sufficient time for the reaction toproceed to completion, and that very long reaction time did not resultin product degradation. All conditions tested gave comparable Compound11 yield and purity.

The conditions identified as optimal were then tested together in asingle reaction. These experimental conditions used THF as solvent, 50°C. reaction temperature, and CBz-Lys-NCA addition over 4 hrs, followedby an additional 2 hours of stirring prior to product isolation. Usingthese conditions, recrystallized Compound 11 was recovered in 55.8%yield, with a purity of 97.75 wt %. Unwanted oligomer formation was notobserved using these conditions.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about”. Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained bythe present invention. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of the invention areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. Any numerical value, however,inherently contains certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

The terms “a” and “an” and “the” and similar references used in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext.

Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is hereindeemed to contain the group as modified thus fulfilling the writtendescription of any and all Markush groups used in the appended claims.

The invention claimed is:
 1. A method for the synthesis of adiketopiperazine, the method comprising mixing a cyclic amino compoundaccording to the following formula:

with a catalyst in an organic solvent and heating the mixture, wherein Ris a C1 to C8 N-protected alkyl amine, wherein the protecting group isselected from the group consisting of amide forming protecting groupsand carbamate forming protecting groups and wherein X is selected fromC, P, and S.
 2. The method of claim 1, wherein the organic solvent isselected from THF, acetonitrile, dioxane, and ethanol.
 3. The method ofclaim 1, wherein the catalyst is present in an amount of 0.25 to 2.5equivalents based on the amount of the cyclic amino compound.
 4. Themethod of claim 1, wherein the catalyst is selected from aziridine,benzamidoxime, 4-nitrobenzamidoxime, hydroxysuccinimide, p-nitrophenol,and hydroxybenzotriazole.
 5. The method of claim 1, wherein the catalystis an amine catalyst.
 6. The method of claim 1, wherein R is—(CH₂)_(n)-NHPG, wherein n is 3-5.
 7. The method of claim 6, wherein PGis selected from acetyl, trichloroacetyl, trifluoroacetyl,benzyloxycarbonyl (Cbz) and t-butoxycarbonyl (Boc).
 8. The method ofclaim 7, wherein PG is selected from trifluoroacetyl, Cbz, and Boc. 9.The method of claim 8, wherein PG is trifluoroacetyl.
 10. The method ofclaim 1, wherein X is C.
 11. The method of claim 1, wherein X is P. 12.The method of claim 1, wherein X is S.
 13. A method for the synthesis ofa diketopiperazine, the method comprising mixing a cyclic amino compoundaccording to the following formula:

with a catalyst in an organic solvent and heating the mixture, whereinPG is selected from the group consisting of amide forming protectinggroups and carbamate forming protecting groups and wherein X is selectedfrom C, P, and S.
 14. The method of claim 13, wherein the organicsolvent is selected from THF, acetonitrile, dioxane, and ethanol. 15.The method of claim 13, wherein the organic solvent is selected from THFand ethanol.
 16. The method of claim 13, wherein the catalyst isselected from aziridine, benzamidoxime, 4-nitrobenzamidoxime,hydroxysuccinimide, p-nitrophenol, and hydroxybenzotriazole.
 17. Themethod of claim 13, wherein the catalyst is present in an amount of 0.25to 2.5 equivalents based on the amount of cyclic amino compound.
 18. Themethod of claim 13, wherein PG is selected from acetyl, trichloroacetyl,trifluoroacetyl, benzyloxycarbonyl (Cbz) and t-butoxycarbonyl (Boc). 19.The method of claim 13, wherein PG is trifluoroacetyl.
 20. The method ofclaim 13, wherein X is C.